A major goal of this laboratory is to understand the molecular mechanisms by which the nuclear hormone receptor peroxisome proliferator-activated receptor ? (PPAR?) controls adipogenesis and mediates antidiabetic effects of thiazolidinedione (TZD) drugs that improve insulin sensitivity but cause unwanted side effects. We hypothesize that target gene- and tissue- selective modulation of gene expression by PPAR? are dictated by different modes of PPAR? binding and synergy between PPAR? and cooperating transcription factors.
Specific Aim 1 is to determine the direct transcriptional effect of TZDs in adipocytes and their relation to PPAR? binding on a genome-wide scale. We hypothesize that the direct effects of TZDs on transcription cannot be predicted from transcriptomic analysis. Preliminary Global Run-On sequencing (GRO-seq) results demonstrate the feasibility of measuring nascent transcripts in adipocytes on a genome-wide scale.
Specific Aim 2 is to delineate the adipocyte epigenome and corepressor cistromes, and their relation to PPAR? binding and the effects of TZD treatment on a genome-wide scale. We hypothesize that TZD treatment of adipocytes alters coregulator recruitment to PPAR? at a subset of target genes, leading to epigenomic changes that alter gene transcription. This will be tested by ChIP-seq for coregulators and epigenomic marks in adipocytes treated with TZDs and non-TZD ligands with potentially fewer side effects.
Specific Aim 3 is to understand the mechanisms of cell-type specific genomic binding and regulation by PPAR?. We hypothesize that PPAR? functions as a pioneer factor on some binding sites, particularly in adipocytes, whereas macrophage binding sites are more influenced by cell- specific transcription factors and epigenomic marks. This will be tested using cistromic approaches, and the ability of PPAR? and cell type-specific factors such as PU.1 to shape each other's genomic binding, as well as the adipocyte and macrophage epigenomes, will be explored using gain and loss of function studies. Our innovative approach will elucidate mechanisms underlying target gene- and tissue-specificity of PPAR?, which can be translated to the design of more selective insulin sensitizers to combat the epidemic of metabolic disorders.

Public Health Relevance

The epidemic of type 2 diabetes is related to obesity-related insulin resistance. Drugs that work via the nuclear receptor PPAR?, which regulates gene expression in fat cells, powerfully increase insulin sensitivity but have side effects that limit teir use. These studies will elucidate mechanisms by which PPAR? regulates gene expression, that facilitate the design of safer, more effective insulin sensitizers.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Molecular and Cellular Endocrinology Study Section (MCE)
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Margolis, Ronald N
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University of Pennsylvania
Internal Medicine/Medicine
Schools of Medicine
United States
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Lazar, Mitchell A (2018) Reversing the curse on PPAR?. J Clin Invest 128:2202-2204
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